Coated implantable medical device

ABSTRACT

A medical device ( 10 ) includes a structure ( 12 ) adapted for introduction into a patient, the structure ( 12 ) being formed of a preferably non-porous base material ( 14 ) having a roughened or textured surface ( 16 ). The structure ( 12 ) is conveniently configured as a vascular stent with a base material ( 14 ) of stainless steel, nitinol or another suitable material. The medical device ( 10 ) also includes a layer ( 18 ) of a bioactive material posited directly upon the roughened or textured surface ( 16 ) of the base material ( 14 ) of the structure ( 12 ). The surface ( 16 ) of the base material ( 14 ) is roughened or textured by etching or by abrasion with sodium bicarbonate or another suitable grit. A preferred roughened or textured surface ( 16 ) is thought to have a mean surface roughness of about 10 μin. (about 250 nm) and a surface roughness range between about 1 μin. and about 100 μin. (about 25 nm and about 2.5 μm). The particularly preferred use of sodium bicarbonate as the abrasive to provide roughness or texture to the surface ( 16 ) of the base material ( 14 ) of the structure ( 12 ) is additionally advantageous in the low toxicity of the sodium bicarbonate to production workers, the ease of product and waste cleanup, and the biocompatibility of any residual sodium bicarbonate.

RELATED APPLICATION INFORMATION

This application claims priority from U.S. Provisional Application Ser.No. 60/244,446 filed Oct. 31, 2000.

TECHNICAL FIELD

This invention relates generally to human and veterinary medical devicesand, more particularly, to devices incorporating drugs, bioactiveagents, therapeutic agents or diagnostic agents.

BACKGROUND OF THE INVENTION

It has become common to treat a variety of medical conditions bytemporarily or permanently introducing an implantable medical devicepartly or completely into the esophagus, trachea, colon, biliary tract,urinary tract, vascular system or other location within a human orveterinary patient. Many treatments of the vascular or other systemsentail the introduction of a device such as a stent, a catheter, aballoon, a wire guide, a cannula or the like. For this purpose, a stentmay most simply be considered as a cylinder of relatively short lengthwhich opens a body passage or lumen or which maintains a body passage orlumen in an open condition.

Such medical devices are generally capable of serving their intendedpurposes quite well. Some drawbacks can be encountered during their use,however. For example, when a device is introduced into and manipulatedthrough the vascular system of a patient, the blood vessel walls can bedisturbed or injured. Clot formation or thrombosis often results at theinjured site, causing stenosis (closure) of the blood vessel. Moreover,if the medical device is left within the patient for an extended periodof time, thrombus often forms on the device itself, again causingstenosis. As a result, the patient is placed at risk of a variety ofcomplications, including heart attack, pulmonary embolism, and stroke.Thus, the use of such a medical device can entail the risk of preciselythe problems that its use was intended to ameliorate.

Another way in which blood vessels undergo stenosis is through disease.Probably the most common disease causing stenosis of blood vessels isatherosclerosis. Many medical devices and therapeutic methods are knownfor the treatment of atherosclerotic disease. One particularly usefultherapy for certain atherosclerotic lesions is percutaneous transluminalangioplasty (PTA). During PTA, a balloon-tipped catheter is inserted ina patient's artery, the balloon being deflated. The tip of the catheteris advanced to the site of the atherosclerotic plaque to be dilated. Theballoon is placed within or across the stenotic segment of the artery,and then inflated. Inflation of the balloon “cracks” the atheroscleroticplaque and expands the vessel, thereby relieving the stenosis, at leastin part.

While PTA presently enjoys wide use, it suffers from two major problems.First, the blood vessel may suffer acute occlusion immediately after orwithin the initial hours after the dilation procedure. Such occlusion isreferred to as “abrupt closure.” Abrupt closure occurs in perhaps fivepercent or so of the cases in which PTA is employed, and can result inmyocardial infarction and death if blood flow is not restored promptly.The primary mechanisms of abrupt closures are believed to be elasticrecoil, arterial dissection and/or thrombosis. It has been postulatedthat the delivery of an appropriate agent (such as an antithrombic)directly into the arterial wall at the time of angioplasty could reducethe incidence of thrombotic acute closure, but the results of attemptsto do so have been mixed.

A second major problem encountered in PTA is the re-narrowing of anartery after an initially successful angioplasty. This re-narrowing isreferred to as “restenosis” and typically occurs within the first sixmonths after angioplasty. Restenosis is believed to arise through theproliferation and migration of cellular components from the arterialwall, as well as through geometric changes in the arterial wall referredto as “remodeling.” It has similarly been postulated that the deliveryof appropriate agents directly into the arterial wall could interruptthe cellular and/or remodeling events leading to restenosis. However,like the attempts to prevent thrombotic acute closure, the results ofattempts to prevent restenosis in this manner have been mixed.

Non-atherosclerotic vascular stenosis may also be treated by PTA. Forexample, Takayasu arteritis or neurofibromatosis may cause stenosis byfibrotic thickening of the arterial wall. Restenosis of these lesionsoccurs at a high rate following angioplasty, however, due to thefibrotic nature of the diseases. Medical therapies to treat or obviatethem have been similarly disappointing.

A device such as an intravascular stent can be a useful adjunct to PTA,particularly in the case of either acute or threatened closure afterangioplasty. The stent is placed in the dilated segment of the artery tomechanically prevent abrupt closure and restenosis. Unfortunately, evenwhen the implantation of the stent is accompanied by aggressive andprecise antiplatelet and anticoagulation therapy (typically by systemicadministration), the incidence of thrombotic vessel closure or otherthrombotic complication remains significant, and the prevention ofrestenosis is not as successful as desired. Furthermore, an undesirableside effect of the systemic antiplatelet and anticoagulation therapy isan increased incidence of bleeding complications, most often at thepercutaneous entry site.

Other conditions and diseases are treatable with stents, catheters,cannulae and other medical devices inserted into the esophagus, trachea,colon, biliary tract, urinary tract and other locations in the body. Awide variety of bioactive materials (drugs, therapeutic agents,diagnostic agents and other materials having biological orpharmacological activity within a patient) have been applied to suchmedical devices for the purpose of introducing such materials into thepatient. Unfortunately, the durable application of bioactive materialsto stents and the like, sufficient for such introduction to successfullyoccur, is often problematic. A range of containment or layeringmaterials have been applied to such devices to permit the timed releaseof bioactive materials from such devices, or even to permit bioactivematerials to be applied to such devices at all. Unfortunately, the useof such containment materials can significantly increase the time andcost of manufacturing suitable implantable devices. Moreover, somebioactive materials may not be able to withstand incorporation in knowncontainment materials. Additionally, certain containment materials maynot be biocompatible and may cause problems of the type desired to bereduced.

It would be desirable to develop devices and methods for reliablydelivering suitable therapeutic and diagnostic agents, drugs and otherbioactive materials directly into a body portion during or following amedical procedure, so as to treat or prevent the conditions and diseasesmentioned above, for example, to prevent abrupt closure and/orrestenosis of a body portion such as a passage, lumen or blood vessel.It would also be desirable to limit systemic exposure of the patient tosuch bioactive materials. This would be particularly advantageous intherapies involving the delivery of a chemotherapeutic agent to aparticular organ or site through an intravenous catheter (which itselfhas the advantage of reducing the amount of agent needed for successfultreatment), by preventing stenosis both along the catheter and at thecatheter tip. It would be desirable to similarly improve othertherapies. Of course, it would also be desirable to avoid degradation ofthe agent, drug or bioactive material during its incorporation on orinto any such device. It would further be highly desirable to develop amethod for coating an implantable medical device with a drug,therapeutic agent, diagnostic agent or other bioactive material whichentailed a minimum number of steps, thereby reducing the ultimate costof treating the patient.

It would be desirable to deliver the bioactive material without causingadditional problems with a poor biocompatible carrier or containmentmaterial. Finally, it would be highly desirable to develop a method forcoating an implantable medical device with a drug, therapeutic agent,diagnostic agent or other bioactive material which could be carried outin such a way as to minimize any environmental or personal risks orinconveniences associated with the manufacture of the device.

SUMMARY OF THE INVENTION

The foregoing problems are solved and a technical advance is achieved inan illustrative embodiment of a medical device of the present inventioncoated (at least in part) with a drug, therapeutic agent, diagnosticagent or other bioactive or pharmacologically active material.(Hereinafter, any or all of these will be collectively referred to as “abioactive material ” or “bioactive materials.”). The specificimprovement of the present invention entails attaining a desired surfaceroughness, or texturing, on the surface of the device by whatevertreatment of the surface and applying the bioactive material directly tothat roughened or textured surface without the need of any furtheroverlying or containment layer or coating. Unexpectedly, thisstraightforward expedient yields a coated implantable medical devicewhich is sufficiently durable to withstand the desired implantationwithout suffering an unacceptable amount of loss (if any) of bioactivematerial from the device. In one aspect of the invention, at least apart of the surface of the device, for example the outer surface of astent, is treated to produce a roughened, uneven, or unsmooth surface,and the bioactive material is formed or posited on at least the part ofthe surface. The degree of surface treatment is controlled to providesufficient adhesion of the bioactive material to the device surface.

In the preferred embodiment of the medical device of the presentinvention, the device first comprises a structure adapted for temporaryor permanent introduction into the esophagus, trachea, colon, biliarytract, urinary tract, vascular system or other location in a human orveterinary patient. The structure comprises a base material (preferablynon-porous) having a roughened or textured surface. The surface of thebase material can be roughened or textured by etching but is preferablyroughened or textured by abrasion with an abrasive grit, most preferablysodium bicarbonate (USP).

The medical device of the present invention also comprises a layer ofbioactive material posited directly upon the roughened or texturedsurface of the base material of the structure. Furthermore, the deviceadvantageously does not require or is free of any additional coating orlayer atop the layer of bioactive material.

As described in more detail below, the base material of the structureand the bioactive material posited on that base material can compriseany of a wide range of suitable materials. The selection of a specificcombination of base material, bioactive material and surface roughnessor texture depends upon the intended use of the medical device. Althoughtexture may have a meaning of a repeatable pattern, this is clearly notthe intent. The surface of the stent is that of any topography, whetherrepeatable or not, that helps improve adhesion of the bioactive materialon the base material or modification thereof. Hereinafter, a texturedsurface will include a roughened, uneven, or unsmooth surface. Thesuitability of a chosen combination can readily be determined by anadhesion test which simulates the actual delivery of bioactive materialduring introduction and deployment of the device in a patient. Such atest is straightforward and is believed not to entail an undue amount ofexperimentation, particularly in comparison to the amount and technicallevel of testing required before a product of this type can be marketedin the United States.

The medical device of the present invention and its method ofmanufacture have several advantages over prior stents and other medicaldevices and methods for manufacturing them. The time and cost ofmanufacture of the medical device are minimized by the absence of anysteps to incorporate the bioactive material in a containment layer, orto apply a containment or time-release layer over the bioactivematerial. The particularly preferred use of sodium bicarbonate as theabrasive to treat, roughen, or texture the surface of the base materialof the structure enjoys several indirect cost savings resulting from thelow toxicity of the sodium bicarbonate to production workers, the easeof product and waste cleanup, and the biocompatibility of any residualsodium bicarbonate. Worker safety and ease of product and waste cleanupare, of course, important advantages in their own right.

In a first aspect, then, the present invention is directed to a medicaldevice comprising: a structure adapted for introduction into a patient,the structure comprising a base material (preferably non-porous) havinga at least one of a roughened, uneven, unsmooth, or textured surface;and a layer of a bioactive material posited directly upon the surface ofthe base material of the structure. Furthermore, the medical device doesnot require or is free of any additional coating or layer atop the layerof bioactive material for delivering the bioactive material. Thestructure is preferably configured as a stent, such as a vascular orother stent.

The base material of the structure preferably comprises at least one of:stainless steel, tantalum, titanium, nitinol, gold, platinum, inconel,iridium, silver, tungsten, or another biocompatible metal, or alloys ofany of these; carbon or carbon fiber; cellulose acetate, cellulosenitrate, silicone, polyethylene terephthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these.

The bioactive material of the layer on the roughened, uneven, unsmooth,or textured surface of the base material preferably comprises at leastone of: paclitaxel; estrogen or estrogen derivatives; heparin or anotherthrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-pol-L-arginyl chloromethyl ketone or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopdineor another antiplatelet agent; colchicine or another antimitotic, oranother microtubule inhibitor; cytochalasin or another actin inhibitor;a remodelling inhibitor; deoxyribonucleic acid, an antisense nucleotideor another agent for molecular genetic intervention; GP IIb/IIIa, GPIb-IX or another inhibitor or surface glycoprotein receptor;methotrexate or another antimetabolite or antiproliferative agent; ananti-cancer chemotherapeutic agent; dexamethasone, dexamethasone sodiumphosphate, dexamethasone acetate or another dexamethasone derivative, oranother anti-inflammatory steroid; dopamine, bromocriptine mesylate,pergolide mesylate or another dopamine agonist; ⁶⁰Co (having a half lifeof 5.3 years), ¹⁹²Ir (73.8 days), ³²P (14.3 days), ¹¹¹In (68 hours), ⁹⁰Y(64 hours), ^(99m)Tc (6 hours) or another radiotherapeutic agent;iodine-containing compounds, barium-containing compounds, gold,tantalum, platinum, tungsten or another heavy metal functioning as aradiopaque agent; a peptide, a protein, an enzyme, an extracellularmatrix component, a cellular component or another biologic agent;captopril, enalapril or another angiotensin converting enzyme (ACE)inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase,deferoxyamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxidant; angiopeptin; a ¹⁴C-, ³H-,¹³¹I-, ³²P-or ³⁶S-radiolabelled form or other radiolabelled form of anyof the foregoing; or a mixture of any of these.

Preferably, the roughened, uneven, unsmooth, or textured surface of thebase material of the structure has a mean surface roughness of about 10μin. (about 250 nm) and a surface roughness range between about 1 μin.and about 100 μin. (about 25 nm and about 2.5 μm).

In a second aspect, the present invention is directed to a medicaldevice comprising: a structure adapted for introduction into a patient,the structure comprising a base material having a roughened, uneven,unsmooth, or textured surface, the structure being configured as avascular stent and the base material comprising at least one ofstainless steel, nitinol, or an allow of nickel and titanium; and alayer of a bioactive material posited directly upon the roughened ortextured surface of the base material of the structure, the bioactivematerial comprising paclitaxel; wherein the medical device does notrequire or is free of any additional coating or layer atop the layer ofbioactive material; and wherein the roughened or textured surface of thebase material of the structure has a mean surface roughness of about 10μin. (about 250 nm) and a surface roughness range between about 1 μin.and about 100 μin. (about 25 nm and about 2.5 μm).

In a third aspect, the present invention is directed to a method ofmanufacturing a medical device comprising the steps of: providing astructure adapted for introduction into a patient, the structurecomprising a base material (preferably non-porous) having a surface;roughening or texturing the surface of the base material of thestructure; and positing a layer of a bioactive material directly uponthe roughened or textured surface of the base material of the structure;the method being characterized in that the resulting medical device doesnot require or is free of any additional coating or layer atop the layerof bioactive material.

Preferably, the method is carried out with a structure configured as astent, such as a vascular stent. The method is preferably carried outwith a base material and a bioactive material as described in the firstaspect of the invention above.

The positing step of the method is preferably carried out by spraying asolution of the bioactive material on the roughened or textured surfaceof the base material of the structure. Dipping the base material in asolution of the bioactive material is also contemplated in the practiceof the present invention.

The roughening or texturing step of the method is preferably carried outby abrading the surface of the base material of the structure. Etchingof the surface is also contemplated in the practice of the presentinvention.

Abrading of the surface of the base material is preferably carried outwith an abrasive grit comprising at least one of sodium bicarbonate(USP), calcium carbonate, aluminum oxide, colmanite (calcium borate),crushed glass or crushed walnut shells. More preferably, the abrading iscarried out with an abrasive grit having a particle size of about 5microns (5 μm) to about 500 microns (500 μm). Even more preferably, theabrading is carried out with sodium bicarbonate (USP) having a nominalparticle size of about 50 microns (50 μm).

Abrading of the surface of the base material is preferably carried outwith an abrasive grit delivered at a pressure under flow of about 5 toabout 200 PSI (about 34 to about 1380 KPa) and at a grit feed rate ofabout 1 to about 1000 g/min. Abrading of the surface is preferablycarried out so as to yield a textured surface on the base materialhaving a mean surface roughness of about 10 μin. (about 250 nm) and asurface roughness range between about 1 μin. and about 100 μin. (about25 nm and about 2.5 μm).

In another aspect, the present invention is directed to the product ofthe method described in the third aspect of the invention, above. In yeta further aspect, the present invention is directed to a method ofmedical treatment or diagnosis which comprises introducing the medicaldevice of the present invention, or the product of the method of thepresent invention, into a human or veterinary patient.

Again, as indicated above, the medical device of the present inventionand its method of manufacture have several advantages over prior stentsand other medical devices and methods for manufacturing them. The timeand cost of manufacture of the medical device of the present inventionare minimized by the absence of any steps to incorporate the bioactivematerial in a containment layer, or to apply a containment ortime-release layer over the bioactive material. The particularlypreferred use of sodium bicarbonate as the abrasive to roughen ortexture the surface of the base material of the structure enjoys costsavings resulting from the low toxicity of the sodium bicarbonate toproduction workers, the ease of product and waste cleanup, and thebiocompatibility of any residual sodium bicarbonate. It should gowithout saying that the good worker safety and ease of product and wastecleanup enjoyed by the method of the present invention are highlydesirable advantages, without regard to any costs saved.

BRIEF DESCRIPTION OF THE DRAWING

A better understanding of the present invention will now be had uponreference to the following detailed description, when read inconjunction with the accompanying drawing, wherein like referencecharacters refer to like parts throughout the several views, and inwhich:

FIG. 1 is a side view showing one of the steps of the method of thepreferred embodiment of the present invention; and

FIG. 2 is an enlarged cross-sectional view of a portion of the medicaldevice and product of the preferred embodiment of the present invention.

DETAILED DESCRIPTION

With reference now to the Figures, an implantable medical device 10 inaccordance with the present invention is there shown. The medical device10 of the present invention first comprises a structure 12 adapted fortemporary or permanent introduction into a human or veterinary patient.“Adapted” means that the structure 12 is particularly configured, shapedand sized for such introduction. By way of example, the structure 12 ismost preferably configured as a vascular stent adapted for insertioninto the vascular system of the patient.

The structure 12 can of course be particularly configured for use inother systems and sites such as the esophagus, trachea, colon, biliaryducts, urethra and ureters, among others. Indeed, the structure 12 canalternatively be configured as any conventional vascular or othercomparable medical device, and can include any of a variety ofconventional stent or other adjuncts, such as helically wound strands,perforated cylinders or the like. Moreover, because the problemsaddressed by the present invention arise primarily with respect to thoseportions of the device actually positioned within the patient, theinserted structure 12 need not be an entire device, but can merely bethat portion of a vascular or other device which is intended to beintroduced into the patient. Accordingly, the structure 12 can beconfigured as at least one of, or any portion of, a catheter, a wireguide, a cannula, a stent, a vascular or other graft, a cardiacpacemaker lead or lead tip, a cardiac defibrillator lead or lead tip, aheart valve, a suture, a needle, an angioplasty device or a pacemaker.The structure 12 can also be configured as a combination of portions ofany of these.

For ease of understanding the present invention, FIGS. 1 and 2 show onlya structure 12 configured as a stent, and more particularly, a vascularstent. More preferably, the structure 12 is configured as a vascularstent such as the “LOGIC” stent, the “V-FLEX PLUS” stent, or the“ACHIEVE” stent, all commercially available from Cook Incorporated,Bloomington, Ind. Such stents are cut from a cannula of suitablematerial and possess a plurality of interconnected struts allowing thestents to expand upon inflation of a balloon on which they are carried.They possess a flat outer surface, which as a practical matter makesthem easier to process via the present invention than stents made of aplurality of round wires; the latter are more difficult to abrade. Thesestents possess a smooth inside surface to reduce the possibility ofthrombogenesis.

The particular shape and dimensions of the structure 12 should of coursebe selected as required for its specific purpose and for the particularsite in the patient at which it will be employed, such as in thecoronary arteries, aorta, esophagus, trachea, colon, biliary tract orurinary tract. A structure 12 intended for each location will havedifferent dimensions particularly suited to such use. For example,aortic, esophageal, tracheal and colonic stents may have diameters up toabout 25 mm and lengths about 100 mm or longer. Vascular stents aregenerally shorter, typically about 10 to 60 mm in length, and oftenpreferably about 12 to 25 mm in length. Such vascular stents aretypically designed to expand to a diameter of about 2 to 6 mm wheninserted into the vascular system of a patient, often preferably about 2to 4 mm.

The structure 12 is composed of a base material 14 suitable for theintended use of the structure 12. The base material 14 is preferablybiocompatible. A variety of conventional materials can be employed asthe base material 14. Some materials may be more useful for structuresother than the coronary stent exemplifying the structure 12. The basematerial 14 may be either elastic or inelastic as required for itsintended use in the patient. The base material may be eitherbiodegradable or nonbiodegradable, and a variety of biodegradablepolymers are known. The base material 14 can also be porous orpreferably non-porous, again based on its intended use or application.

Accordingly, the base material 14 can include at least one of stainlesssteel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium,silver, tungsten, or another biocompatible metal, or alloys of any ofthese; carbon or carbon fiber; cellulose acetate, cellulose nitrate,silicone, polyethylene terephthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these. Stainless steel is particularly useful as thebase material 14 when the structure 12 is configured as a vascularstent. In the practice of the present invention, however, particularlypreferred base materials 14 include stainless steel, nitinol, tantalum,polylactic acid, polyglycolic acid and biodegradable materials.Molybdenum-rhenium alloy and magnesium may also possibly be useful basematerials 14 as well.

Of course, when the structure 12 is composed of a radiolucent materialsuch as polypropylene, polyethylene or others above, a conventionalradiopaque marker or coating may and preferably should be applied to itat some limited location. The radiopaque marker or coating provides ameans for identifying the location of the structure 12 by X-ray orfluoroscopy during or after its introduction into the patient's vascularsystem. The base material 14 of the structure 12 of the medical device10 of the present invention includes a roughened or textured surface 16extending at least partly over the base material 14. The surface 16 isroughened or textured in a manner described in more detail below. Whilethe surface 16 can be the entire surface of the base material 14, in thepreferred embodiment of the present invention (where the structure 12 isconfigured as a vascular stent) the surface 16 is the outer surface ofthe base material 14.

The medical device 10 of the present invention further comprises atleast one layer 18 of a bioactive material posited directly upon theroughened or textured surface 16 of the base material 14 of thestructure 12. The medical device 10 of the present invention ischaracterized in that it does not require or is free of any additionalcoating or layer atop the layer 18 of bioactive material. Although, itis to be understood that for any reason an additional coating or layeratop or below the layer 18 of bioactive is desired, such coating orlayer can be applied and still be within the contemplation of thepresent invention. The layer 18 may be smoother or rougher than theroughened or textured surface 16.

The base material 14 of the structure 12 is preferably non-porous,although the structure 12 itself can be perforate. The differencebetween a porous material and a non-porous but perforate material is apractical one; the relatively smaller open cells of a porous materialare of a character and number sufficient to retain an appreciable amountof an applied bioactive material therein, while the relatively largerperforations of a non-porous material are of a character and numberwhich are not sufficient to retain an appreciable amount of an appliedbioactive material therein. Alternatively, the open cells of a porousmaterial can be considered generally microscopic, while perforationsthrough a non-porous material can be considered generally macroscopic.

A vast range of drugs, medicants and materials can be employed as thebioactive material in the layer 18. Particularly useful in the practiceof the present invention are materials which prevent or ameliorateabrupt closure and restenosis of blood vessels previously opened bystenting surgery or other procedures. Thrombolytics (which dissolve,break up or disperse thrombi) and antithrombogenics (which interferewith or prevent the formation of thrombi) are especially usefulbioactive materials when the structure 12 is a vascular stent.Particularly preferred thrombolytics are urokinase, streptokinase andthe tissue plasminogen activators. Particularly preferredantithrombogenics are heparin, hirudin and the antiplatelets.

Urokinase is a plasminogen activating enzyme typically obtained fromhuman kidney cell cultures. Urokinase catalyzes the conversion ofplasminogen into the fibrinolytic plasmin, which breaks down fibrinthrombi.

Heparin is a mucopolysaccharide anticoagulant typically obtained fromporcine intestinal mucosa or bovine lung. Heparin acts as a thrombininhibitor by greatly enhancing the effects of the blood's endogenousantithrombin III. Thrombin, a potent enzyme in the coagulation cascade,is key in catalyzing the formation of fibrin. Therefore, by inhibitingthrombin, heparin inhibits the formation of fibrin thrombi.

Of course, bioactive materials having other functions can also besuccessfully delivered by the device 10 of the present invention. Forexample, an antiproliferative agent such as methotrexate will inhibitover-proliferation of smooth muscle cells and thus inhibit restenosis ofthe dilated segment of the blood vessel. Additionally, localizeddelivery of an antiproliferative agent is also useful for the treatmentof a variety of malignant conditions characterized by highly vasculargrowth. In such cases, the device 10 of the present invention could beplaced in the arterial supply of the tumor to provide a means ofdelivering a relatively high dose of the antiproliferative agentdirectly to the tumor.

A vasodilator such as a calcium channel blocker or a nitrate willsuppress vasospasm, which is common following angioplasty procedures.Vasospasm occurs as a response to injury of a blood vessel, and thetendency toward vasospasm decreases as the vessel heals. Accordingly,the vasodilator is desirably supplied over a period of about two tothree weeks. Of course, trauma from angioplasty is not the only vesselinjury which can cause vasospasm, and the device 10 may be introducedinto vessels other than the coronary arteries, such as the aorta,carotid arteries, renal arteries, iliac arteries or peripheral arteriesfor the prevention of vasospasm in them.

A variety of other bioactive materials are particularly suitable for usewhen the structure 12 is configured as something other than a coronarystent. For example, an anti-cancer chemotherapeutic agent can bedelivered by the device 10 to a localized tumor. More particularly, thedevice 10 can be placed in an artery supplying blood to the tumor orelsewhere to deliver a relatively high and prolonged dose of the agentdirectly to the tumor, while limiting systemic exposure and toxicity.The agent may be a curative, a pre-operative debulker reducing the sizeof the tumor, or a palliative which eases the symptoms of the disease.It should be noted that the bioactive material in the present inventionis delivered across the device 10, and not by passage from an outsidesource through any lumen defined in the device 10, such as through acatheter employed for conventional chemotherapy. The bioactive materialof the present invention may, of course, be released from the device 10into any lumen defined in it, and that lumen may carry some other agentto be delivered through it.

Paclitaxel is a particularly preferred anti-cancer agent and/orantiangiogenic agent as the bioactive material of the layer 18. Theangiogenesis-dependent diseases are those diseases which require orinduce vascular growth, for example, certain types of cancer. Estrogenand estrogen derivatives are also particularly preferred as thebioactive material of the layer 18.

Dopamine or a dopamine agonist such as bromocriptine mesylate orpergolide mesylate is useful for the treatment of neurological disorderssuch as Parkinson's disease. The device 10 could be placed in thevascular supply of the thalamic substantia nigra for this purpose, orelsewhere, localizing treatment in the thalamus.

The present invention also contemplates the use of bioactive materialswhich covalently bond to the roughened or textured surface 16 of thebase material 14 of the structure 12.

It should be clear that a wide range of other bioactive materials can bedelivered by the device 10. Accordingly, it is preferred that thebioactive material of the layer 18 comprises at least one of:paclitaxel; estrogen or estrogen derivatives; heparin or anotherthrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopdineor another antiplatelet agent; colchicine or another antimitotic, oranother microtubule inhibitor; cytochalasin or another actin inhibitor;a remodelling inhibitor; deoxyribonucleic acid, an antisense nucleotideor another agent for molecular genetic intervention; GP IIb/IIIa, GPIb-IX or another inhibitor or surface glycoprotein receptor;methotrexate or another antimetabolite or antiproliferative agent; ananti-cancer chemotherapeutic agent; dexamethasone, dexamethasone sodiumphosphate, dexamethasone acetate or another dexamethasone derivative, oranother anti-inflammatory steroid; an immunosuppressive agent (such ascyclosporin or rapamycine); an antibiotic (such as streptomycin,erythromycin or vancomycine); dopamine, bromocriptine mesylate,pergolide mesylate or another dopamine agonist; ⁶⁰Co (having a half lifeof 5.3 years), ¹⁹²Ir (73.8 days), ³²P (14.3 days), ¹¹¹In (68 hours), ⁹⁰Y(64 hours), ^(99m)Tc (6 hours) or another radiotherapeutic agent;iodine-containing compounds, barium-containing compounds, gold,tantalum, platinum, tungsten or another heavy metal functioning as aradiopaque agent; a peptide, a protein, an enzyme, an extracellularmatrix component, a cellular component or another biologic agent;captopril, enalapril or another angiotensin converting enzyme (ACE)inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase,deferoxyamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxideint; angiopeptin; ¹⁴C-, ³H-, ¹³¹I-,³²P- or ³⁶S-radiolabelled form or other radiolabelled form of any of theforegoing; or a mixture of any of these.

When the structure 12 is configured as a vascular stent, however,particularly preferred materials for the bioactive material of the layer18 are heparin, anti-inflammatory steroids including but not limited todexamethasone and its derivatives, and mixtures of heparin and suchsteroids.

Other materials may possibly be useful as the bioactive material in thepractice of the present invention, including: smooth muscle cellinhibitors, collagen inhibitors, anti-coagulants and cholesterolreducing agents; forskolin, vapiprost, prostaglandin and analoguesthereof, prostacyclin and prostacyclin analogues, dextran anddipyridamole; angiotensin converting enzyme inhibitors such asCaptopril® (available from Squibb), Cilazapril® (available fromHoffman-LaRoche), or Lisinopril® (available from Merck); fibroblastgrowth factor (FGF) antagonists, fish oil (omega 3-fatty acid),histamine antagonists, Lovastatin® (an inhibitor of HMG-CoA reductase, acholesterol-lowering drug from Merck), methotrexate, monoclonalantibodies (such as to PDGF receptors), nitroprusside, phosphodiesteraseinhibitors, prostaglandin inhibitor (available from Glaxo), vascularendothelial growth factor (VEGF) or analogues thereof, various cellcycle inhibitors such as the protein product of the retinoblastoma tumorsuppressor gene or analogues thereof), Seramin (a PDGF antagonist),serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide, alpha-interferonand genetically engineered epithelial cells.

The present invention is also directed to a method of manufacturing themedical device 10 disclosed above. More particularly, the method of thepresent invention first comprises providing a structure 12 adapted forthe temporary or permanent introduction into a patient. The structure 12comprises a preferably non-porous base material 14 having a surface 16and is configured, for example, as a stent (such as a vascular stent).The structure 12 and the base material 14 have been described in detailabove, and for brevity, such details will not be repeated here.Stainless steel, nitinol, tantalum, polylactic acid, polyglycolic acidand biodegradable materials are particularly preferred as the basematerial 14 of the structure 12.

The method of the present invention further comprises the steps ofattaining a desired roughness or texture on the surface 16 of the basematerial 14 of the structure 12, and positing a layer 18 of a bioactivematerial directly upon the roughened or textured surface 16 of the basematerial 14. A wide range of bioactive materials useful in the layer 18has been disclosed in detail above; again, for brevity, such detail willnot be repeated. Paclitaxel, a taxane or another paclitaxel analogue,estrogen and estrogen derivatives are particularly preferred asbioactive materials in the layer 18.

The method of manufacturing a medical device 10 according to the presentinvention is characterized in that the resulting medical device 10 doesnot require or is free of any additional coating or layer atop the layer18 of bioactive material. The method of the present invention thereforedoes not include any steps in which the bioactive material is covered byor contained within a time-release or containment layer. While themethod of the present invention contemplates the use of a base material14 which itself comprises a plurality of layers or constituents, such anarrangement may not be preferred in the practice of the presentinvention. In any event, it would be the outermost one of such plurallayers or constituents which possesses the roughened or textured surface16 on which the layer 18 of bioactive material is posited directly.

The step of directly positing the layer 18 of bioactive material on theroughened or textured surface 16 of the base material 14 can be carriedout in any convenient manner. The structure 12 (or suitable portionthereof) can be dipped or soaked in an appropriate solution of thedesired bioactive material, and the solvent of the solution evaporatedto leave a layer 18 of the bioactive material on the roughened ortextured surface 16 of the base material 14. Preferably, however, thepositing step is carried out by spraying a solution of the bioactivematerial on the roughened or textured surface 16 of the base material 14of the structure 12 and allowing the structure 12 to dry. While sprayingmay have a relatively low efficiency in transferring the bioactivematerial to the roughened or textured surface 16, it is adequate for thepurposes of the present invention.

By way of example, paclitaxel (the particularly preferred bioactivematerial in the present invention) can be posited by spraying anethanolic solution of it on the roughened or textured surface 16 of thebase material 14. The solution conveniently contains about 2 to about 4mg of paclitaxel per ml of ethanol. (The ethanol should be 100% USPgrade or equivalent, not denatured alcohol or 95% ethanol.) Taking astent of 15 mm in length and 3 mm in diameter as typical, having atextured, gross outer surface area on the order of 25 mm², spraying canbe readily carried out to posit about 5 to about 500 μg, preferably 50to 150 μg, of paclitaxel on the roughened or textured surface 16 of thebase material 14. Perhaps less than about 1% of the paclitaxel isultimately posited from solution onto the textured surface 16. Theselection of suitable solvents and concentrations for other bioactivematerials, or the selection of other techniques for positing otherbioactive materials directly upon the roughened or textured surface 16,should be well within the skill of those in the art in view of thepresent disclosure. Any experimentation required should be minimal,particularly in view of the extensive testing required before devices ofthis type can be distributed in the U.S.

The surface 16 of the base material 14 of the structure 12 can beroughened or textured in any convenient manner, such as by etching.Preferably, however, the surface 16 is roughened or textured byabrading, for example, by abrading with an abrasive grit 24 comprisingat least one of sodium bicarbonate (USP), calcium carbonate, aluminumoxide, colmanite (calcium borate), crushed glass, crushed walnut shells,or mixtures of these or other abrasive particulates. Such roughening ortexturing is most easily carried out by placing the medical device 10 ona mandrel 20 in a position such that abrasive grit 24 delivered from anozzle 22 impinges on the surface 16. The initial surface of the basematerial prior to roughening or texturing may be smoother than thedesired surface roughness, or it may be even rougher.

The grit size and feed rate of the abrasive grit 24, the structure ofthe nozzle 22, the pressure at which the abrasive grit 24 is deliveredfrom the nozzle 22, the distance of the surface 16 from the nozzle 22and the rate of relative movement of the medical device and the nozzle22 are all factors to be considered in achieving an appropriate desiredroughness; or texture of the surface 16 of the base material 14 of thestructure 12. By way of non-limiting example, when the base material 14is stainless steel, the abrading step can be carried out with anabrasive grit 24 having a particle size of about 5 microns (5 μm) toabout 500 microns (500 μm). More preferably, the abrading step iscarried out with sodium bicarbonate (USP) having a nominal particle sizeof about 50 microns (50 μm), with approximately 50% greater than 40microns (40 μm) and approximately 1% greater than 150 microns (150 μm).Such abrading is preferably carried out with the sodium bicarbonate orother abrasive grit 24 delivered at a pressure under flow of about 5 toabout 200 PSI (about 34 to about 1380 KPa), most preferably about 100PSI (about 690 KPa). Such abrading is also preferably carried out withthe sodium bicarbonate or other abrasive grit 24 delivered at a gritfeed rate of about 1 to about 1000 g/min, most preferably about 10 toabout 15 g/min.

The carrier gas or propellant for delivery of the abrasive grit ispreferably nitrogen, air or argon, and most preferably nitrogen,although other gases may be suitable as well. When the medical device 10is configured as disclosed above, the distance from the outlet of thenozzle 22 to the center of the mandrel 20 can be about 1 to about 100mm. A preferred nozzle 22 is the Comco Microblaster; when employed, thepreferred distance from the outlet of the nozzle 22 to the center of themandrel 20 is about 5 to about 10 mm. The Paasche LAC #3 is also usefulas the nozzle 22.

To provide a uniform roughening or texturing of the surface 16 of thebase material 14 of the structure 12, it is highly desirable thatrelative movement of the surface 16 and the nozzle 22 be provided duringabrasion of the surface 16. Any pattern of motion which achieves thedesired uniformity of roughness or texture may be employed. It ispreferred that such motion entail both longitudinal or lengthwisemovement along the structure 12 and circumferential movement orrepositioning about the structure 12. Repeated longitudinal movementwith repeated passes at different circumferential positions is mostpreferable. More particularly, abrading of the surface 16 can entailfrom 1 to about 50 axial passes per circumferential position, while thenumber of circumferential positions for such axial passes can range fromabout 4 to an unlimited number of circumferential positions. This lastis achieved by continuous relative rotation of the surface 16 and thenozzle 22. The sweep rate of the nozzle 22 along the surface 16 canrange from about 1 to about 70 mm/sec for the particular stentdimensions disclosed above.

When the base material 14 of the structure 12 is stainless steel, andthe abrasive grit 24 is 50 micron sodium bicarbonate (USP), aparticularly preferred combination of abrading conditions is:

-   -   Nozzle 22: Comco Microblaster    -   Propellant: Nitrogen gas    -   Pressure: 120 PSI (828 KPa) (under flow)    -   Spray plan: 8 equally-spaced circumferential positions 4 axial        passes per circumferential position    -   Sweep rate: About 16 mm/sec    -   Grit feed rate: About 0.15 to 0.30 g/sec    -   Nozzle outlet to mandrel center: about 5 to 10 mm

When abrading is carried out in this manner, a roughened or texturedsurface 16 is obtained which is thought to have a mean surface roughness(that is, a mean height of surface features) of about 10 μin. (about 250nm) and a surface roughness range between about 1 μin. and about 100μin. (about 25 nm and about 2.5 μm). Such a surface 16 is capable ofretaining on it a highly substantial portion of bioactive materialposited directly on it without requiring any additional covering orcontainment layer.

More particularly, the adhesion of paclitaxel to two types of stainlesssteel, grit abraded stents was compared to its adhesion to stents ofthose types whose surfaces had instead been plasma treated prior to thedirect deposition of paclitaxel thereon (control stents). The coatedstents of both types, that is, medical devices 10 of the presentinvention and control stents, were then subjected to a physical adhesiontest which simulated the rate at which paclitaxel would be deliveredduring introduction and deployment of the stents in clinical use. Theadhesion test involved passing each stent through a water-filled guidingcatheter of appropriate diameter and inflating the balloon catheter toexpand each stent to its intended diameter. The stents are alreadymounted before coating. The amount of paclitaxel remaining on each stentwas then measured by spectrometry and compared to the amount ofpaclitaxel initially posited on each stent. Stents having surfaces 16roughened or textured by abrasion with different abrasive grits 24retained 84.1±10.2% of the paclitaxel originally applied, while stentshaving plasma treated surfaces retained only 44.3±8.7% of the paclitaxeloriginally applied (p<0.0001). This appears to demonstrate thesuccessful retention of the layer 18 of bioactive material on theroughened or textured surface 16 of the base material 14 of thestructure 12 of the medical device 10 of the present invention.

In view of the foregoing disclosure, those skilled in the art shouldreadily be able to perform any trial-and-error testing to obtain theoptimal processing conditions for any desired combination of particularbase materials 14 and bioactive materials. Such testing simply requiresroughening or texturing the surface 16 of a particular base material 14in a selected manner, applying a layer 18 of a particular bioactivematerial to the roughened or textured surface 16 and measuring theretention of bioactive material on the roughened or textured surface 16after clinical introduction and deployment has been mimicked.

It should be clear that the present invention provides a medical device10 and method for manufacturing the same which is particularlyadvantageous over prior devices and methods for making such devices. Thetime and cost of manufacture of the medical device of the presentinvention are minimized by the absence of any steps to incorporate thebioactive material in a containment layer, or to apply a containment ortime-release layer over the bioactive material. The particularlypreferred use of sodium bicarbonate as the abrasive to provide roughnessor texture to the surface of the base material of the structure isadvantageous in the low toxicity of the sodium bicarbonate to productionworkers, the ease of product and waste cleanup, and the biocompatibilityof any residual sodium bicarbonate. These are important advantages intheir own right, but incidentally also reduce the time and cost formanufacture of the medical device 10.

The details of the construction or composition of the various elementsof the medical device of the present invention not otherwise disclosedare not believed to be critical to the achievement of the advantages ofthe present invention, so long as the elements possess the strength ormechanical properties needed for them to perform as disclosed. Theselection of any such details of construction are believed to be wellwithin the ability of one of even rudimentary skills in this area, inview of the present disclosure. For practical reasons, however, mostembodiments of the medical device 10 of the present invention shouldprobably be considered to be single-use devices, rather than beingreusable.

INDUSTRIAL APPLICABILITY

The present invention is useful in the performance of various surgicalprocedures and in the manufacture of devices for the performance ofvarious surgical procedures, and therefore finds applicability in humanand veterinary medicine.

It is to be understood, however, that the above-described device ismerely an illustrative embodiment of the principles of this invention,and that other devices and methods for using them may be devised bythose skilled in the art, without departing from the spirit and scope ofthe invention. It is also to be understood that the invention isdirected to embodiments both comprising and consisting of the disclosedparts. In particular, it is contemplated that only part of a medicaldevice 10 according to the present invention need be coated withbioactive material. It is further contemplated that different parts of amedical device 10 could be coated with different bioactive materials.

It is also to be understood that various parts, recesses, portions,sides, segments, channels, and the like of the device can be positedwith the bioactive material either singly or in combination with otherbioactive, coating, or layering materials. This can be done to furthercontrol the release of the bioactive material to the delivery site. Suchconfigurations are contemplated and disclosed in U.S. Pat. Nos.5,380,299; 5,609,629; 5,824,049; 5,873,904; 6,096,070; 6,299,604 and areincorporated by reference herein. Likewise, presently pending patentapplications claiming priority to these patents such as Ser. Nos.08/956,715; 09/027,054; and 09/850,691 are also contemplated andincorporated by reference herein.

As previously suggested, the medical device of the present invention canalso include channels, grooves, recesses, indentations, projections,buildups, and the like to increase the surface area of the device towhich the bioactive material can be posited therein.

1. A medical device for introduction into a patient, comprising: a stenthaving a surface, at least part of the surface having been treated toproduce a roughened, uneven, unsmooth, or textured surface having a meansurface roughness of about 10 μin. (about 250 nm) and a surfaceroughness range between about 1 μin. and about 100 μin. (about 25 nm andabout 2.5 μm), and a bioactive material on at least said part of thesurface.
 2. The medical device according to claim 1, wherein saidroughened, uneven, unsmooth, or textured surface provides sufficientadhesion of the bioactive material thereon.
 3. A medical devicecomprising; a structure adapted for introduction into a patient, thestructure being configured as a vascular stent and comprising a basematerial having at least one of a roughened, uneven, unsmooth, ortextured surface having a mean surface roughness of about 10 μin. (about250 nm and a surface roughness range between about 1 μin. and about 100μin. (about 25 nm and about 2.5 μm); and a layer of a bioactive materialposited directly upon the at least one surface of the base material ofthe structure.
 4. The medical device according to claim 3, wherein thebase material of the structure comprises at least one of: stainlesssteel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium,silver, tungsten, or another biocompatible metal, or alloys of any ofthese; carbon or carbon fiber; cellulose acetate, cellulose nitrate,silicone, polyethylene terephtalate, polyurethane, polyamide, polyester,polyorthoester, polyanhydride, polyether sulfone, polycarbonate,polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or another biocompatible polymeric material, ormixtures or copolymers of these; polylactic acid, polyglycolic acid orcopolymers thereof, a polyanhydride, polycaprolactone,polyhydroxybutyrate valerate or another biodegradable polymer, ormixtures or copolymers of these; a protein, an extracellular matrixcomponent, collagen, fibrin or another biologic agent; or a suitablemixture of any of these.
 5. The medical device according to claim 3,wherein the bioactive material of the layer comprises at least one of:paclitaxel, a taxane or other paclitaxel analogue; estrogen or estrogenderivatives; heparin or another thrombin inhibitor, hirudin, hirulog,argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, oranother antithrombogenic agent, or mixtures thereof; urokinase,streptokinase, a tissue plasminogen activator, or another thrombolyticagent, or mixtures thereof; a fibrinolytic agent; a vasospasm inhibitor;a calcium channel blocker, a nitrate, nitric oxide, a nitric oxidepromoter or another vasodilator; an antimicrobial agent or antibiotic;aspirin, ticlopdine or another antiplatelet agent; vascular endothelialgrowth factor (VEGF) or analogues thereof; colchicine or anotherantimitotic, or another microtubule inhibitor; cytochalasin or anotheractin inhibitor; a remodeling inhibitor; deoxyribonucleic acid, anantisense nucleotide or another agent for molecular geneticintervention; a cell cycle inhibitor (such as the protein product of theretinoblastoma tumor suppressor gene, or analogues thereof); GPIIb/IIIa, GP Ib-IX or another inhibitor or surface glycoproteinreceptor; methotrexate or another antimetabolite or anti-proliferativeagent; an anti-cancer chemotherapeutic agent; dexamethasone,dexamethasone sodium phosphate, dexamethasone acetate or anotherdexamethasone derivative, or another anti-inflammatory steroid;prostaglandin, prostacyclin or analogues thereof; an immunosuppressiveagent (such as cyclosporine or rapamycin); an antibiotic (such asstreptomycin), erythromycin or vancomycin; dopamine, bromocriptinemesylate, pergolide mesylate or another dopamine agonist; ⁶⁰Co, ¹⁹²Ir,³²P, ¹¹¹In, ⁹⁰Y, ^(99m)Tc or another radiotherapeutic agent;iodine-containing compounds, barium-containing compounds, gold,tantalum, platinum, tungsten or another heavy metal functioning as aradiopaque agent; a peptide, a protein, an enzyme, an extracellularmatrix component, a cellular component or another biologic agent;captopril, enalapril or another angiotensin converting enzyme (ACE)inhibitor; ascorbic acid, alphatocopherol, superoxide dismutase,deferoxyamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxidant; angiopeptin; a ¹⁴C-, ³H-,¹³¹I-, ³²P- or ³⁶S-radiolabelled form or other radiolabelled form of anyof the foregoing; or a mixture of any of these.
 6. The medical deviceaccording to claim 3, wherein the medical device does not require or isfree of any additional coating or layer atop the layer of bioactivematerial.
 7. A medical device comprising: a structure adapted forintroduction into a patient, the structure comprising a base materialhaving at least one of a roughened, uneven, unsmooth, or texturedsurface, the structure being configured as a vascular stent and the basematerial comprising at least one of stainless steel, nitinol, and analloy of nickel and titanium; and a layer of a bioactive materialposited directly upon the at least one surface of the base material ofthe structure, the bioactive material comprising paclitaxel; wherein themedical device does not require any additional coating or layer atop thelayer of bioactive material; and wherein the at least one surface of thebase material of the structure has a mean surface roughness of about 10μin. (about 250 nm) and a surface roughness range between about 1 μin.and about 100 μin. (about 25 nm and about 2.5 μm).